17-41363874-G-A

Variant names:

• chr17-41363874-G-A
• rs202226873
• NM_002279.5:c.1177C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002279.5(KRT33B):​c.1177C>T​(p.Arg393Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,452 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (2 hom.)
• Consequence: KRT33B NM_002279.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94
• Publications: 3 publications found

Genes affected

KRT33B (HGNC:6451): (keratin 33B) This gene encodes a member of the keratin gene family. This gene is one of multiple type I hair keratin genes that are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. As a type I hair keratin, the encoded protein is an acidic protein which heterodimerizes with type II keratins to form hair and nails. There are two isoforms of this protein, encoded by two separate genes, keratin 33A and keratin 33B. [provided by RefSeq, May 2012]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19912288).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002279.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT33B	NM_002279.5	MANE Select	c.1177C>T	p.Arg393Cys	missense	Exon 7 of 7	NP_002270.1	Q14525

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT33B	ENST00000251646.8	TSL:1 MANE Select	c.1177C>T	p.Arg393Cys	missense	Exon 7 of 7	ENSP00000251646.3	Q14525

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250432 AF XY: 0.00

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460322 Hom.: 2 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726418

African (AFR) AF: 0.000211 AC: 7 AN: 33154

American (AMR) AF: 0.00 AC: 0 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111402

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151130 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73810

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000247 AC: 1 AN: 40458

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000106 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.080	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.21
Sift	Benign	0.055	T
Sift4G	Benign	0.095	T
Polyphen		0.0010	B
Vest4		0.52
MutPred		0.34		Gain of catalytic residue at P392 (P = 0.009)
MVP		0.37
MPC		0.45
ClinPred		0.095	T
GERP RS		3.9
Varity_R		0.060
gMVP		0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202226873; hg19: chr17-39520126; COSMIC: COSV52442056;